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Mitochondrial miRNA494-3p in extracellular vesicles participates in cellular interplay of iPS-Derived human retinal pigment epithelium with macrophages.

Authors
  • Mukai, Atsushi1
  • Otsuki, Yohei1
  • Ito, Eiko1
  • Fujita, Tomoko1
  • Ueno, Morio1
  • Maeda, Tadao2
  • Kinoshita, Shigeru3
  • Sotozono, Chie1
  • Hamuro, Junji4
  • 1 Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto 602-0841, Japan. , (Japan)
  • 2 Kobe Eye Center Hospital, 2-1-8 Minatojima-minami-cho, Chuo-ku, Kobe, 650-0047, Japan. , (Japan)
  • 3 Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan. , (Japan)
  • 4 Department of Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Hirokoji-agaru, Kawaramachi-dori, Kamigyo-ku, Kyoto 602-0841, Japan. Electronic address: [email protected] , (Japan)
Type
Published Article
Journal
Experimental Eye Research
Publisher
Elsevier
Publication Date
Jul 01, 2021
Volume
208
Pages
108621–108621
Identifiers
DOI: 10.1016/j.exer.2021.108621
PMID: 34000275
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

To explore new molecular targets for therapy in human model systems by discerning the role of extracellular vesicle (EV) microRNAs (miRs) secreted by human retinal pigment epithelium (hRPE) cells and their cellular interplay with macrophages (Mps). Human Mps differentiated from THP-1 cells stimulated by phorbol myristate acetate were co-cultured with induced pluripotent stem cell-derived differentiated hRPE (iPS-hRPE) cells in Transwell® system separated by 0.40 μm or 0.03 μm filters. EV-associated CD63+ proteins (CD63+ EV) were detected by western blotting, and secreted EVs were analyzed by Nanosight tracking. The miR profiles of the secreted EVs were determined using 3D-gene human microRNA chips (Toray Industries, Inc.). Levels of CD63+ EV were increased in co-cultures concomitantly with the increased production of EV particles (50-150 nm). The increased production of EVs was associated with higher production of MCP-1, IL-6, IL-8 from hRPE cells, and VEGF and repressed production of TNF-α from Mps and pigment epithelium-derived factor (PEDF) from RPE cells. Ultracentrifugation of semi-purified EVs increased the secretion of these pro-inflammatory cytokines and EV particles from hRPE cells, but this effect was eliminated in transwells equipped with 0.03 μm filters, whereas no repression of PEDF and TNF-α secretion occurred. 3D-gene miR analysis revealed a selective increase in secretion of miR494-3p in EVs from iPS-hRPE cells during the interplay with Mps. The miRs in EVs secreted by hRPE cells may have a critical role in the vicious inflammatory cycle, whereas repression of TNF-α and PEDF require cell-to-cell contact that is independent of EVs or exosomes. MiR494-3p may be a candidate molecular target of diagnosis and therapy for age-related macular degeneration. Copyright © 2021 Elsevier Ltd. All rights reserved.

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